When access to food is unrestricted, the constraint of having to oxidize a metabolic fuel mix containing as much fat as the diet plays a more important role in determining body fat than overall energy expenditure. The main goal of the proposed investigations is to test the implications of this concept in understanding the causes for the high incidence of obesity in affluent societies. Using a unique method to establish daily and cumulative carbohydrate and fat balances over many consecutive days, which combines 24-h respiratory gas exchange, food intake and spontaneous running activity measurements, we have demonstrated that weight maintenance in ad libitum fed mice is brought about by modulation of food intake, and that this serves primarily the need to maintain carbohydrate rather than energy balance. We now propose to determine whether this is the case in genetically obese mice as well, and whether dietary fat also raises their body fat content in a dose-dependent manner. To compare the effectiveness of low-fat diets in reversing obesity induced by high-fat diets, the changes in body fat content which they elicit will be followed using a new plethysmographic method for body density measurements in live animals. Next we propose to study whether variables known to influence body fat content, such as pregnancy, exercise, glucocorticoids or their antagonists, drugs and cold exposure, do so through their impact on the RQ and the carbohydrate economy, and thereby on food intake, and to which extent these effects may be influenced by the diet's fat content. In particular we will test the hypothesis that fat accumulation during pregnancy is due in part to the increment in food intake needed to compensate for the increasing amounts of glucose oxidized by the fetus, and that this accumulation may be altered by changing the diet's fat content. Whole-body considerations suggest that the opposing actions of insulin and FFA concentrations on pyruvate oxidation are likely to play a crucial role in limiting or promoting the development of obesity and that the usual influence of increases in the adipose tissue mass in restricting pyruvate oxidation fails to occur in cases of extreme obesity. To see how adjustment of pyruvate oxidation is brought about in vivo, the amounts of food provided to normal and genetically obese mice will be restricted, thereby forcing them to operate at the same average 24-h RQ. Comparisons of daily RQ patterns to assess carbohydrate dissipation after the feeding period, and measurements of glycogen levels and body fat content by chemical carcass analysis will be used to examine how the body composition of genetically obese animals has to differ to bring about appropriate restraint on pyruvate oxidation. These investigations will contribute to the body of knowledge from which dietary recommendations most susceptible to facilitate weight maintenance at lower levels of adiposity can be formulated.